JP2018090510A - Orally disintegrable tablet containing duloxetine hydrochloride - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an orally disintegrable tablet containing duloxetine hydrochloride that can be taken more comfortably due to a reduced rough taste in the oral cavity and has improved acid resistance.SOLUTION: An orally disintegrable tablet contains a granule composed of: (a) a nuclear particle composed of mannitol with a particle size of more than 150 μm and less than 250 μm, (b) a main agent layer obtained by coating the nuclear particle with duloxetine hydrochloride, (c) a separation layer coating the main agent layer, and (d) an enteric-coated layer obtained by coating the separation layer with an enteric-coated polymer.SELECTED DRAWING: None

Description

  The present invention relates to an orally disintegrating tablet containing duloxetine hydrochloride.

Duloxetine hydrochloride is a serotonin / noradrenaline reuptake inhibitor (SNRI) approved for the indication of major depressive disorder, and is formulated as a capsule with a core containing sucrose / starch spherical granules. It is marketed (see Non-Patent Document 1).
Patent Document 1 discloses a duloxetine preparation comprising a core containing duloxetine; and an enteric coating containing hydroxypropylmethylcellulose phthalate. More specifically, duloxetine pellets and capsule formulations comprising a core comprising duloxetine hydrochloride, globular sugar and popidone; and an enteric coating comprising hypromellose phthalate are disclosed (see Patent Document 1). .

Special table 2010-530868

Cymbalta Capsule Interview Form

  However, the particle size of sucrose / starch spherical granules and spherical sugars used in the cores of Non-Patent Document 1 and Patent Document 1 is only produced with a particle diameter larger than 355 μm. When it was formulated into a disintegrating tablet, roughness in the oral cavity was generated, and there was a problem that the feeling of administration was reduced.

  The present invention has been made in view of the circumstances as described above. In order to reduce roughness in the oral cavity, an orally disintegrating tablet containing duloxetine hydrochloride having improved dosing feeling and excellent acid resistance The purpose is to provide.

The present invention is as follows.
[1] (a) a core particle composed of mannitol having a particle size of more than 150 μm and less than 250 μm;
(B) an active ingredient layer in which the core particles are coated with duloxetine hydrochloride;
(C) a separation layer covering the active ingredient layer;
(D) an enteric layer covering the separation layer;
An orally disintegrating tablet comprising granules consisting of

  INDUSTRIAL APPLICABILITY The present invention can provide an orally disintegrating tablet containing duloxetine hydrochloride having improved dosing feeling and excellent acid resistance.

  The orally disintegrating tablet containing duloxetine hydrochloride according to the present invention has improved dosage feeling and excellent acid resistance by using core particles of mannitol having a particle size of more than 150 μm and less than 250 μm. It has the advantage that an orally disintegrating tablet containing can be obtained.

Orally disintegrating tablet of the present invention,
(A) a core particle composed of mannitol having a particle size of greater than 150 μm and less than 250 μm;
(B) an active ingredient layer in which the core particles are coated with duloxetine hydrochloride as an active ingredient;
(C) a separation layer covering the active ingredient layer;
(D) an enteric layer covering the separation layer;
An orally disintegrating tablet comprising granules consisting of
The orally disintegrating tablet of the present invention may further contain other components or other layers as necessary, as long as the effects of the present invention are not impaired.

  The orally disintegrating tablet of the present invention is superior in acid resistance because it improves the feeling of dosing and suppresses aggregation of particles by using core particles that are mannitol having a particle size of more than 150 μm and less than 250 μm. Orally disintegrating tablets containing duloxetine hydrochloride can be obtained.

(Nuclear particles)
The core particle functions as a granulation core.
Usually, the core particles used are those used as excipients, for example, sucrose / starch, spherical sugar, and microcrystalline cellulose.
However, sucrose / starch spherical granules and spherical sugars are only produced with a particle size larger than 355 μm, and when they are formulated into orally disintegrating tablets using the particle size, roughening occurs in the oral cavity. And the feeling of taking may be reduced.
Moreover, since the starch of sucrose / starch spherical granules and microcrystalline cellulose have water-insoluble properties, the dissolution property of duloxetine hydrochloride may be reduced.

Therefore, the present inventors examined using mannitol having water-soluble properties as a core particle.
The core particle of the present invention is preferably mannitol having a particle size of more than 150 μm and less than 250 μm.
When mannitol core particles having a particle size of 150 μm or less are used, since the mass of one particle is light, static electricity is generated and the particles are aggregated. Therefore, in the enteric coating step, the enteric coating agent cannot be uniformly coated on the entire particle surface, and the acid resistance may decrease.
In addition, since the specific surface area of the particles increases, the amount of enteric coating agent increases, and the film formability and workability may decrease.
On the other hand, when mannitol core particles having a particle diameter of 250 μm or more are used, roughness in the oral cavity may occur, and the feeling of dosing may be reduced.
From the above results, it is preferable to use mannitol having a particle size of more than 150 μm and less than 250 μm, preferably a particle size of 190 μm to 230 μm, and more preferably a particle size of 190 μm to 210 μm.

  Moreover, it is preferable that content of the said mannitol with respect to duloxetine hydrochloride is 80 to 95 mass%, and it is still more preferable that it is 85 to 93 mass%.

  Examples of the particle diameter measuring method include a laser diffraction particle size distribution measuring method, and specific examples include a method using a laser diffraction scattering particle size distribution measuring device (SALD-2300 type, manufactured by Shimadzu Corporation).

(Main drug layer)
The main agent layer is a layer that covers the core particles and is provided outside the core particles.
It contains duloxetine hydrochloride as the active ingredient in the active ingredient layer. Duloxetine hydrochloride is a general name (S)-(+)-N-methyl-3- (1-naphthyloxy) -3- (2-thienyl) propylamine hydrochloride and has the following molecular structure: .

Duloxetine hydrochloride is preferably crystalline, and has a volume average particle diameter (D50) of 1 μm to 50 μm, preferably 2 μm to 25 μm, and more preferably 2 μm to 10 μm.
This is because the layering efficiency is improved when the volume average particle size is in the above range.
As a measuring method of the volume average particle size (D50), there is a laser diffraction particle size distribution measuring method, and a specific example is a method using a laser diffraction scattering particle size distribution measuring device (SALD-2300 type, manufactured by Shimadzu Corporation). Is mentioned.

The active ingredient layer can contain a polymer, for example, a water-soluble polymer.
The water-soluble polymer contained in the active ingredient layer is not particularly limited as long as it is a component that can be dissolved in any of acidic, neutral, and alkaline solutions without depending on the pH value of the solution in contact with it. Can be used.
In the present specification, the water-soluble polymer means a polymer having a solubility in water at 20 ° C. of 10 g / L or more.

Specific examples of the water-soluble polymer include water-soluble cellulose derivatives, water-soluble vinyl polymer derivatives, water-soluble acrylic acid copolymers, polyhydric alcohol polymers, and copolymers thereof. Preferably, a water-soluble cellulose derivative and a water-soluble vinyl polymer derivative are mentioned, More preferably, a water-soluble cellulose derivative is mentioned.
More specifically, examples of the water-soluble cellulose derivative include hydroxypropyl methylcellulose, methylcellulose, and hydroxypropylcellulose. Examples of the water-soluble vinyl polymer derivative include polyvinyl alcohol and polyvinyl pyrrolidone.
Examples of the water-soluble acrylic acid copolymer include polymers that contain acrylic acid, acrylic acid ester, methacrylic acid ester, and the like and that can be dissolved in any of acidic, neutral, and alkaline aqueous solutions.
Examples of the polyhydric alcohol polymer include macrogol or polyglycerin. Examples of the copolymer of these polymers include polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, polyethylene glycol polyvinyl alcohol graft copolymer, vinyl pyrrolidone / vinyl alcohol copolymer, and the like.
Among these, hydroxypropylmethylcellulose and hydroxypropylcellulose are preferable as the water-soluble polymer from the viewpoints of viscosity and binding properties suitable for fine particle coating.
Any one water-soluble polymer may be used alone, or two or more water-soluble polymers may be used in combination.

  The content of the water-soluble polymer contained in the active ingredient layer can be appropriately determined in consideration of the content of duloxetine hydrochloride, the daily dose, the particle diameter, and the like. For example, the content of the water-soluble polymer can be 100% by mass or less, preferably 10% by mass or more and 50% by mass or less, with respect to the total mass of the coating component constituting the active ingredient layer. % To 20% by mass or less is more preferable.

  Other ingredients contained in the active ingredient layer include ingredients that can function as excipients that improve moldability and convenience, components that can function as binders that contribute to improved moldability, and promote disintegration of the formulation Ingredients that can function as disintegrants, and components that can function as lubricants and fluidizing agents that contribute to improved productivity.

  Specific examples of the component that can function as an excipient for improving moldability and convenient administration include sugar, sugar alcohol, crystalline cellulose, and starch. Examples of the sugar include lactose, sucrose, maltose, trehalose, dextrin and the like. Examples of the sugar alcohol include mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol and the like. Examples of the starch include corn starch, potato starch, rice starch, wheat starch and the like.

  Examples of the component that can function as a binder that contributes to improvement of moldability include hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, and polyvinylpyrrolidone.

  As a component that can function as a disintegrant that promotes disintegration, a known disintegrant can be used. For example, starch such as corn starch and potato starch, partially pregelatinized starch, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, low substituted hydroxypropyl cellulose, crystalline cellulose, hydroxypropyl starch, sodium starch glycolate, etc. Can be mentioned.

  Examples of components that can function as a lubricant or a fluidizing agent that contribute to the improvement of manufacturability include talc and light anhydrous silicic acid.

  The form in which the active ingredient layer is coated with the core particles may be a state in which the active ingredient layer is present on at least a part of the surface of the core particle. The main agent layer preferably covers 1/4 or more of the surface of the core particle, and more preferably covers 1/2 or more. Most preferably, the active ingredient layer covers the entire surface of the core particle.

The coating amount of the main drug layer when coating the core particles with the main drug layer is not particularly limited as long as the core particles are coated in the main drug layer. For example, the mass of the active ingredient layer used for coating the core particles is 0.01 times to 50 times, 0.1 times to 5 times, or 0.5 times the total weight of the core particles. It is mentioned that it is more than the amount and less than 3 times.
In forming the active ingredient layer, 0.01 times to 50 times, 0.1 times to 5 times, or 0.5 times the amount of the core particles based on the mass. What is necessary is just to melt | dissolve or suspend the component which comprises the active ingredient layer of the mass 3 times or less above in a pharmacologically acceptable solvent, and to spray on a core particle.

(Separation layer)
The separation layer is a layer that covers the main drug layer and prevents contact between the enteric layer and the main drug layer. The separation layer can include a polymer, for example, a water-soluble polymer, a water-insoluble polymer, an alkaline polymer, and the like. Further, the separation layer may be a multilayer such as two layers or three layers as will be described later, but is preferably composed of a single layer.

The water-soluble polymer contained in the separation layer is not particularly limited as long as it is a component that can be dissolved in any of acidic, neutral and alkaline solutions without depending on the pH value of the solution to be contacted. Can be used.
The water-soluble polymer is preferably a water-soluble polymer that does not hinder the elution of the coated active ingredient after the enteric layer covering the separation layer is dissolved in the intestine.
In the present specification, the water-soluble polymer means a polymer having a solubility in water at 20 ° C. of 10 g / L or more.

Specific examples of the water-soluble polymer include water-soluble cellulose derivatives, water-soluble vinyl polymer derivatives, water-soluble acrylic acid copolymers, polyhydric alcohol polymers, and copolymers thereof. Preferably, a water-soluble cellulose derivative and a water-soluble vinyl polymer derivative are mentioned, More preferably, a water-soluble cellulose derivative is mentioned.
More specifically, examples of the water-soluble cellulose derivative include hydroxypropyl methylcellulose, methylcellulose, and hydroxypropylcellulose. Examples of the water-soluble vinyl polymer derivative include polyvinyl alcohol and polyvinyl pyrrolidone.
Examples of the water-soluble acrylic acid copolymer include polymers that contain acrylic acid, acrylic acid ester, methacrylic acid ester, and the like and that can be dissolved in any of acidic, neutral, and alkaline aqueous solutions.
Examples of the polyhydric alcohol polymer include macrogol or polyglycerin. Examples of the copolymer of these polymers include polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, polyethylene glycol polyvinyl alcohol graft copolymer, vinyl pyrrolidone / vinyl alcohol copolymer, and the like.
Among these, hydroxypropylmethylcellulose and hydroxypropylcellulose are preferable as the water-soluble polymer from the viewpoints of viscosity and binding properties suitable for fine particle coating.
Any one water-soluble polymer may be used alone, or two or more water-soluble polymers may be used in combination.

  The content of the water-soluble polymer contained in the separation layer can be appropriately determined in consideration of the content of duloxetine hydrochloride, the daily dose, the particle diameter, and the like. For example, the content of the water-soluble polymer can be 100% by mass or less, preferably 10% by mass or more and 50% by mass or less, with respect to the total mass of the coating component constituting the separation layer. % To 20% by mass or less is more preferable.

The water-insoluble polymer contained in the separation layer is not particularly limited as long as it is a component that does not depend on the pH value of the solution in contact and does not dissolve in any of acidic, neutral and alkaline solutions. Can be used.
Further, the water-insoluble polymer is preferably a polymer that controls the elution of duloxetine hydrochloride, for example, by slowly releasing the coated duloxetine hydrochloride after the enteric layer covering the separation layer is dissolved in the intestine.
In the present specification, the water-insoluble polymer means a polymer having a solubility in water at 20 ° C. of less than 10 g / L.

Examples of the water-insoluble polymer include water-insoluble cellulose ether and water-insoluble acrylic acid copolymer. Examples of the water-insoluble cellulose ether include ethyl cellulose. Examples of the water-insoluble acrylic acid copolymer include ethyl acrylate / methyl methacrylate / methacrylic acid trimethylammonium ethyl copolymer, ethyl acrylate / methyl methacrylate copolymer dispersion, and the like.
As the water-insoluble polymer, any one of the water-insoluble polymers may be used alone, or two or more kinds thereof may be used in combination.

  The content of the water-insoluble polymer contained in the separation layer can be appropriately determined in consideration of the content of duloxetine hydrochloride, the daily dose, the particle diameter, and the like. For example, the content of the water-insoluble polymer can be 100% by mass or less, preferably 10% by mass or more and 50% by mass or less, with respect to the total mass of the coating component constituting the separation layer. % To 20% by mass or less is more preferable.

  The alkaline polymer contained in the separation layer is not particularly limited as long as the polymer aqueous solution or water suspension exhibits alkalinity, and a known polymer can be used. Specifically, it is a polymer in which the pH of an aqueous solution or suspension of polymer is 7.5 or more, preferably 8.5 or more.

Examples of the alkaline polymer include polyvinyl acetal diethylaminoacetate, methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer, methyl methacrylate / diethylaminoethyl methacrylate copolymer, and the like.
As the alkaline polymer, any one of the alkaline polymers may be used alone, or two or more may be used in combination.

  The content of the alkaline polymer contained in the separation layer can be appropriately determined in consideration of the content of duloxetine hydrochloride, the daily dose, the particle diameter, and the like. For example, the content of the alkaline polymer can be 100% by mass or less, preferably 10% by mass or more and 50% by mass or less, with respect to the total mass of the coating component constituting the separation layer. More preferably, it is 20 mass% or less.

  In addition to the polymer, the separation layer may contain other components as long as the effects of the present invention are not impaired. As other ingredients, components that can function as excipients that improve moldability and convenience, components that can function as binders that contribute to improvement of moldability, and disintegrants that promote the disintegration of formulations A component that can function, a component that can function as a lubricant or a fluidizing agent that contributes to an improvement in manufacturability, and the like, and one component may perform two or more functions.

  Specific examples of the component that can function as an excipient for improving moldability and convenient administration include sugar, sugar alcohol, crystalline cellulose, and starch. Examples of the sugar include sucrose, lactose, maltose, trehalose, and dextrin. Examples of the sugar alcohol include mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol and the like. Examples of the starch include corn starch, potato starch, rice starch, wheat starch and the like.

  Examples of the component that can function as a binder that contributes to improvement of moldability include hydroxypropyl cellulose, polyvinyl alcohol, and polyvinyl pyrrolidone.

  A well-known thing can be used as a disintegrating agent. For example, starch such as corn starch and potato starch, partially pregelatinized starch, sodium carboxymethyl starch, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, low substituted hydroxypropyl cellulose, crystalline cellulose, hydroxypropyl starch, etc. Can be mentioned.

  Examples of components that can function as a lubricant or a fluidizing agent that contribute to the improvement of manufacturability include talc and light anhydrous silicic acid.

  Examples of components that can function as a coloring agent that protects coloring and duloxetine hydrochloride from light include titanium oxide, zinc oxide, and iron sesquioxide.

  The form in which the separation layer coats the active ingredient layer may be a state in which the separation layer is present on at least a part of the surface of the active ingredient layer. The separation layer preferably covers 1/4 or more of the surface of the active ingredient layer, and more preferably covers 1/2 or more. Most preferably, the separation layer covers the entire surface of the active ingredient layer.

The coating amount of the separation layer when the main agent layer is coated with the separation layer is not particularly limited as long as it is an amount in which the main agent layer is coated with the separation layer. For example, the mass of the separation layer used for coating the active ingredient layer is 0.01 times or more and 50 times or less, 0.1 times or more and 5 times or less, or 0.5 times the total weight of the active ingredient layer. It is mentioned that it is more than the amount and less than twice the amount.
In forming the separation layer, 0.01 times to 50 times, 0.1 times to 5 times, or 0.5 times the weight of the active ingredient layer based on the weight. What is necessary is just to melt | dissolve or suspend the component which comprises the isolation | separation layer of the mass 2 times or less above in a pharmacologically acceptable solvent, and to spray it on a main drug layer.

As described above, the separation layer may be a multilayer such as two layers or three layers, but is preferably composed of a single layer.
It is because it has the effect that layering efficiency improves by comprising by a single layer.
In the case of providing two or more separated layers, a plurality of separated layer coating liquids having different compositions and the like are divided into a plurality of times for each separated layer coating liquid. Just spray it. For example, the composition of the separation layer coating liquid sprayed directly onto the active ingredient layer is a component that can function as a binder, a component that can function as an excipient, a component that can function as a lubricant, a component that can function as a colorant, And a composition containing water.

(Enteric layer)
The enteric layer is a layer that covers the separation layer, and preferably contains an enteric coating agent. Moreover, the enteric layer should just be comprised from one or more layers, and multilayers, such as two layers, may be sufficient as an enteric layer.

The enteric coating agent is not particularly limited as long as it is an enteric polymer that is substantially insoluble at an acidic pH but is at least partially soluble at an alkaline pH from a weaker acidic pH. The acidic pH indicates a pH of 0.5 or more and 4.5 or less, preferably 1.0 or more and 2.0 or less. The weaker acidic pH to alkaline pH is 5.0 or more and 9.0 or less, preferably 6.0 or more and 7.5 or less.
The fact that the enteric coating agent is soluble means that the solubility in a contacting solution at 20 ° C. is 10 g / L or more.

Examples of the enteric coating agent include enteric cellulose derivatives and enteric (meth) acrylic acid copolymers.
Examples of the enteric cellulose derivative include hydroxypropylmethylcellulose phthalate and carboxymethylethylcellulose.
Examples of enteric (meth) acrylic acid copolymers include methacrylic acid copolymers and acrylic acid copolymers. Specifically, methacrylic acid / methyl methacrylate copolymers, methacrylic acid / ethyl acrylate copolymers Examples thereof include a polymer and a methyl acrylate / methyl methacrylate / methacrylic acid copolymer.
Here, in order to select an appropriate enteric coating agent, the adsorptivity between duloxetine hydrochloride and the enteric coating agent was carried out by the following evaluation test.

<Adsorption test>
The peak area of a solution in which a solution in which 25 mg of duloxetine hydrochloride was dissolved and a solution in which 250 mg of the enteric coating agent shown in Table 1 was mixed was compared with the peak area of a solution containing only duloxetine hydrochloride.

<Measurement procedure for adsorptive evaluation test>
25 mg of duloxetine hydrochloride was weighed out and dissolved in the 2nd liquid of JP dissolution test, the total volume of the liquid was 50 mL, and this liquid was used as sample solution A.
Separately, 250 mg of enteric coating agent was weighed out and dissolved in the second solution of JP dissolution test, the total volume of the solution was 50 mL, and this solution was used as sample solution B.
1 mL of the sample solution A and 10 mL of the sample solution B were weighed, and the second solution of the JP dissolution test was added to make 20 mL. The obtained solution was filtered through a membrane filter having a pore size of 0.45 μm or less, and the filtrate was used as a sample solution.

  Separately, 25 mg of duloxetine hydrochloride was accurately weighed and dissolved in the second solution of JP dissolution test to make the total volume of the solution 50 mL. 1 mL of this solution was weighed, and a test solution was further added to make 20 mL, which was used as a standard solution.

Each of the sample solution and standard solution 10μL a were weighed accurately, were tested by liquid chromatography under the following test conditions, the peak area was determined A _T and A _S of duloxetine.
[Test conditions]
Detector: UV absorptiometer (measurement wavelength: 230 nm)
Column: A stainless tube having an inner diameter of 4.6 mm and a length of 100 mm is filled with 5 μm of octylsilylated silica gel for liquid chromatography.
Column temperature: constant temperature around 45 ° C. Mobile phase: 3.4 g of potassium dihydrogen phosphate and 15 mL of triethylamine are dissolved in 1000 mL of water, and phosphoric acid is added to adjust to pH 5.5. To 600 mL of this solution, 300 mL of methanol and 100 mL of tetrahydrofuran are added.
Flow rate: Adjust so that the retention time of duloxetine is about 7 minutes.

[System compatibility]
System performance: When 10 μL of the standard solution is operated under the above conditions, the number of theoretical plates and the symmetry factor of the duloxetine peak are 2000 or more and 2.0 or less, respectively.
System reproducibility: When the test is repeated 6 times with 10 μL of the standard solution under the above conditions, the relative standard deviation of the ratio of the peak area of duloxetine is 2.0% or less.

The adsorption rate was calculated by the following formula.
Adsorption rate (%) = ((peak area of sample solution) / (peak area of standard solution) −1) × 100

The measurement results are shown in Table 1. From the results of Table 1, it was found that the adsorption rate of methacrylic acid copolymer L of Test Example 6 at pH 6.8 was −48.69%, and the adsorption rate of duloxetine hydrochloride was the highest.
On the other hand, hypromellose phthalate ester (HP-50) of Test Example 1, hypromellose phthalate ester (HP-55) of Test Example 2 and hypromellose phthalate ester succinate (AS-) of Test Example 4 The adsorption rate of MF) at pH 6.8 was -10.00% or less, and it was found that the adsorption rate of duloxetine hydrochloride was suppressed.
Further, the adsorption rate at pH 6.8 of the hypromellose phthalate ester (HP-50) of Test Example 1 and the hypromellose phthalate ester (HP-55) of Test Example 2 is suppressed to −8.50% or less. I found out.
Furthermore, the adsorption rate at pH 6.8 of the hypromellose phthalate ester (HP-55) of Test Example 2 was −7.57%, and it was found that the adsorption rate of duloxetine hydrochloride was most suppressed. .

From the above results, enteric coating agents used in the present invention include hypromellose phthalate (HP-55), hypromellose phthalate (HP-50), hypromellose acetate succinate (AS-). MF) is preferably used, and hypromellose phthalate (HP-55) and hypromellose phthalate (HP-50) are more preferably used.
The content of hypromellose phthalate relative to duloxetine hydrochloride is preferably 100% by mass or more and 200% by mass or less, and more preferably 150% by mass or more and 175% by mass or less.

  The enteric coating agent may be used alone or in combination of two or more components having different properties or two or more components having different properties depending on the purpose. Good. Moreover, when using combining 2 or more types of components, it can also be used, for example so that it may become the form of a multilayered structure.

The enteric layer is an enteric coating agent, an ingredient that can function as a plasticizer that improves the plasticity of the film within a range that does not impair the effects of the present invention, and an excipient that makes it easy to improve moldability and take. Each additive such as a component that can function as a component and a component that can function as a binder that contributes to improvement of moldability can be included.
Here, in order to select an appropriate plasticizer, the adsorbability of duloxetine hydrochloride, enteric coating agent hypromellose phthalate (HP-55), and each plasticizer shown in Table 2 is as follows. The evaluation test was conducted.

<Measurement procedure for adsorptive evaluation test>
25 mg of duloxetine hydrochloride was weighed out and dissolved in the 2nd liquid of JP dissolution test, the total volume of the liquid was 50 mL, and this liquid was used as sample solution A.
Separately, weigh 50 mg of enteric coating agent, hypromellose phthalate (HP-55) and 50 mg of plasticizer, dissolve in JP 2 dissolution solution, and put 1 mL of test solution A in it. Then, the total volume of the liquid was 20 mL, and this liquid was designated as sample solution B.
Sample solution B was filtered through a membrane filter having a pore size of 0.45 μm or less, and the filtrate was used as a sample solution.

  Separately, 25 mg of duloxetine hydrochloride was accurately weighed and dissolved in the second solution of JP dissolution test to make the total volume of the solution 50 mL. 1 mL of this solution was weighed, and the second JP dissolution test solution was added to make 20 mL, which was used as the standard solution.

Each of the sample solution and standard solution 10μL a were weighed accurately, were tested by liquid chromatography under the following conditions, the peak area was determined A _T and A _S of duloxetine.
[Test conditions]
Detector: UV absorptiometer (measurement wavelength: 230 nm)
Column: A stainless tube having an inner diameter of 4.6 mm and a length of 100 mm is filled with 5 μm of octylsilylated silica gel for liquid chromatography.
Column temperature: constant temperature around 45 ° C. Mobile phase: 3.4 g of potassium dihydrogen phosphate and 15 mL of triethylamine are dissolved in 1000 mL of water, and phosphoric acid is added to adjust to pH 5.5. To 600 mL of this solution, 300 mL of methanol and 100 mL of tetrahydrofuran are added.
Flow rate: Adjust so that the retention time of duloxetine is about 7 minutes.

[System compatibility]
System performance: When 10 μL of the standard solution is operated under the above conditions, the number of theoretical plates and the symmetry factor of the peak of duloxetine hydrochloride are 2000 plates or more and 2.0 or less, respectively.
System reproducibility: When the test is repeated 6 times with 10 μL of the standard solution under the above conditions, the relative standard deviation of the ratio of the peak area of duloxetine is 2.0% or less.

The adsorption rate was calculated by the following formula.
Adsorption rate (%) = ((peak area of sample solution) / (peak area of standard solution) −1) × 100

The measurement results are shown in Table 2. From the results of Table 2, the adsorption rate at pH 6.8 of HP-55 + polyoxyethylene polyoxypropylene glycol (Polyxomer 407) of Test Example 12 and HP-55 + light silicic acid anhydride (AdSolider 101) of Test Example 14 is −10. It was 0.000% or more, and it was found that the adsorption rate of duloxetine hydrochloride was high.
On the other hand, the adsorption rate at pH 6.8 of HP-55 + Triethyl citrate of Test Example 9 and HP-55 + Monoleate polyoxyethylene sorbitan (Polysorbate 80) of Test Example 10 is suppressed to −7.00% or less. It was found that the adsorption rate of duloxetine hydrochloride was suppressed.
Moreover, the adsorption rate in pH6.8 of HP-55 + triethyl citrate of Test Example 9 was −6.37, and it was found that the adsorption rate of duloxetine hydrochloride was most suppressed.

From the above results, HP-55 + triethyl citrate, HP-55 + polyoxyethylene sorbitan monooleate (polysorbate 80) is used as the combination of the enteric coating (HP-55) and the plasticizer used in the present invention. It is preferable to use HP-55 + triethyl citrate.
Further, the content of triethyl citrate relative to duloxetine hydrochloride is preferably 10% by mass or more and 50% by mass or less, and more preferably 10% by mass or more and 45% by mass or less.

  Specific examples of other additives that can function as excipients that improve moldability and are convenient to take include sugar, sugar alcohol, crystalline cellulose, and starch.

  Examples of the component that can function as a binder that contributes to improvement of moldability include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, and polyvinylpyrrolidone.

  The form in which the enteric layer covers the separation layer may be a state in which the enteric layer is present on at least a part of the surface of the separation layer. The enteric layer preferably covers 1/4 or more of the surface of the separation layer, and more preferably covers 1/2 or more. Most preferably, the enteric layer covers the entire surface of the separation layer.

  The coating amount of the enteric layer when the separation layer is coated with the enteric layer is not particularly limited as long as the separation layer is in the form of being coated with the enteric layer. For example, the mass of the enteric layer used for coating the separation layer is 0.1 to 15 times, preferably 1 to 5 times the total mass of the separation layer. More preferably, the amount is 1.5 times or more and 3 times or less.

  In forming the enteric layer, it is 0.1 to 15 times and preferably 1 to 5 times the mass of the separation layer, based on the mass. More preferably, the components constituting the enteric layer having a mass of 1.5 times or more and 3 times or less may be dissolved or suspended in a pharmacologically acceptable solvent and sprayed onto the separation layer. When the separation layer is composed of two or more layers, the layer farthest from the main drug layer (the layer closest to the enteric layer) is covered with the enteric layer.

The enteric layer may be composed of one or more layers as described above, and the enteric layer may be two layers or the like.
By providing multiple enteric layers, reducing the amount of ingredients that affect the storage stability of duloxetine hydrochloride, etc., providing layers with different flexibility to prevent fine particle breakage, Since the elution of the active ingredient can be adjusted by providing different layers, the productivity can be improved, and the like, the enteric layer is preferably two or more layers.
When two or more enteric layers are provided, a plurality of enteric layer coating solutions having different compositions and the like may be divided into a plurality of times for each enteric layer coating solution and sprayed onto the separation layer.

(Outermost layer)
The outermost layer is a layer that covers the enteric layer and prevents static electricity, and is an optional layer.
The outermost layer can include a polymer, and can include, for example, a water-soluble polymer, a water-insoluble polymer, an alkaline polymer, and the like. Further, as will be described later, the outermost layer may be a multilayer such as two layers or three layers, but is preferably composed of a single layer.

The water-soluble polymer contained in the outermost layer is not particularly limited as long as it is a component that can be dissolved in any of acidic, neutral and alkaline solutions without depending on the pH value of the solution to be contacted. Can be used.
The water-soluble polymer is preferably a water-soluble polymer that does not hinder the elution of the coated active ingredient after the enteric layer covering the separation layer is dissolved in the intestine.
In the present specification, the water-soluble polymer means a polymer having a solubility in water at 20 ° C. of 10 g / L or more.

Specific examples of the water-soluble polymer include water-soluble cellulose derivatives, water-soluble vinyl polymer derivatives, water-soluble acrylic acid copolymers, polyhydric alcohol polymers, and copolymers thereof. Preferably, a water-soluble cellulose derivative and a water-soluble vinyl polymer derivative are mentioned, More preferably, a water-soluble cellulose derivative is mentioned.
More specifically, examples of the water-soluble cellulose derivative include hydroxypropyl methylcellulose, methylcellulose, and hydroxypropylcellulose. Examples of the water-soluble vinyl polymer derivative include polyvinyl alcohol and polyvinyl pyrrolidone.
Examples of the water-soluble acrylic acid copolymer include polymers that contain acrylic acid, acrylic acid ester, methacrylic acid ester, and the like and that can be dissolved in any of acidic, neutral, and alkaline aqueous solutions.
Examples of the polyhydric alcohol polymer include macrogol or polyglycerin. Examples of the copolymer of these polymers include polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, polyethylene glycol polyvinyl alcohol graft copolymer, vinyl pyrrolidone / vinyl alcohol copolymer, and the like.
Among these, hydroxypropylmethylcellulose and hydroxypropylcellulose are preferable as the water-soluble polymer from the viewpoints of viscosity and binding properties suitable for fine particle coating.
Any one water-soluble polymer may be used alone, or two or more water-soluble polymers may be used in combination.

  The content of the water-soluble polymer contained in the outermost layer can be appropriately determined in consideration of the content of duloxetine hydrochloride, the daily dose, the particle size, and the like. For example, the content of the water-soluble polymer can be 100% by mass or less, preferably 15% by mass or more and 60% by mass or less, with respect to the total mass of the coating component constituting the outermost layer. % To 30% by mass or less is more preferable.

The water-insoluble polymer contained in the outermost layer is not particularly limited as long as it is a component that does not depend on the pH value of the solution in contact and does not dissolve in any of acidic, neutral and alkaline solutions. Can be used.
Further, the water-insoluble polymer is preferably a polymer that controls the elution of duloxetine hydrochloride, for example, by slowly releasing the coated duloxetine hydrochloride after the enteric layer covering the separation layer is dissolved in the intestine.
In the present specification, the water-insoluble polymer means a polymer having a solubility in water at 20 ° C. of less than 10 g / L.

Examples of the water-insoluble polymer include water-insoluble cellulose ether and water-insoluble acrylic acid copolymer. Examples of the water-insoluble cellulose ether include ethyl cellulose. Examples of the water-insoluble acrylic acid copolymer include ethyl acrylate / methyl methacrylate / methacrylic acid trimethylammonium ethyl copolymer, ethyl acrylate / methyl methacrylate copolymer dispersion, and the like.
As the water-insoluble polymer, any one of the water-insoluble polymers may be used alone, or two or more kinds thereof may be used in combination.

  The content of the water-insoluble polymer contained in the outermost layer can be appropriately determined in consideration of the content of duloxetine hydrochloride, the daily dose, the particle size, and the like. For example, the content of the water-insoluble polymer can be 100% by mass or less, preferably 15% by mass or more and 60% by mass or less, with respect to the total mass of the coating component constituting the outermost layer. % To 30% by mass or less is more preferable.

  The alkaline polymer contained in the outermost layer is not particularly limited as long as the polymer aqueous solution or water suspension exhibits alkalinity, and a known polymer can be used. Specifically, it is a polymer in which the pH of an aqueous solution or suspension of polymer is 7.5 or more, preferably 8.5 or more.

Examples of the alkaline polymer include polyvinyl acetal diethylaminoacetate, methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer, methyl methacrylate / diethylaminoethyl methacrylate copolymer, and the like.
As the alkaline polymer, any one of the alkaline polymers may be used alone, or two or more may be used in combination.

  The content of the alkaline polymer contained in the outermost layer can be appropriately determined in consideration of the content of duloxetine hydrochloride, the daily dose, the particle diameter, and the like. For example, the content of the alkaline polymer can be 100% by mass or less, preferably 15% by mass or more and 60% by mass or less, with respect to the total mass of the coating component constituting the outermost layer. More preferably, it is 30 mass% or less.

  In addition to the polymer, the outermost layer may contain other components as long as the effects of the present invention are not impaired. As other ingredients, components that can function as excipients that improve moldability and convenience, components that can function as binders that contribute to improvement of moldability, and disintegrants that promote the disintegration of formulations A component that can function, a component that can function as a lubricant or a fluidizing agent that contributes to an improvement in manufacturability, and the like, and one component may perform two or more functions.

  Specific examples of the component that can function as an excipient for improving moldability and convenient administration include sugar, sugar alcohol, crystalline cellulose, and starch. Examples of the sugar include sucrose, lactose, maltose, trehalose, and dextrin. Examples of the sugar alcohol include mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol and the like. Examples of the starch include corn starch, potato starch, rice starch, wheat starch and the like.

  Examples of the component that can function as a binder that contributes to improvement of moldability include hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, and polyvinylpyrrolidone.

  A well-known thing can be used as a disintegrating agent. For example, starch such as corn starch and potato starch, partially pregelatinized starch, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, low substituted hydroxypropyl cellulose, crystalline cellulose, hydroxypropyl starch, sodium starch glycolate, etc. Can be mentioned.

  Examples of components that can function as a lubricant or a fluidizing agent that contribute to the improvement of manufacturability include talc and light anhydrous silicic acid.

  Examples of components that can function as a coloring agent that protects coloring and duloxetine hydrochloride from light include titanium oxide, zinc oxide, and iron sesquioxide.

  The form in which the outermost layer coats the enteric layer may be a state in which the outermost layer is present on at least a part of the surface of the enteric layer. The outermost layer preferably covers 1/4 or more of the surface of the enteric layer, and more preferably covers 1/2 or more. Most preferably, the outermost layer covers the entire surface of the enteric layer.

The coating amount of the enteric layer when the outermost layer is coated with the enteric layer is not particularly limited as long as it is an amount in which the outermost layer is coated with the enteric layer. For example, the mass of the outermost layer used for coating the enteric layer is 0.01 to 50 times, 0.01 to 5 times, or 0. It is mentioned that they are 05 times or more and 1 time or less.
Further, when forming the outermost layer, it is 0.01 times to 50 times, 0.01 times to 5 times, or 0.05 times based on the total mass of the enteric layer. What is necessary is just to melt | dissolve or suspend the component which comprises the outermost layer of the mass more than the amount of 1 time amount or less in a pharmacologically acceptable solvent, and to spray on an enteric layer.

As described above, the outermost layer may be a multilayer such as two layers or three layers, but is preferably composed of a single layer.
It is because it has the effect that layering efficiency improves by comprising by a single layer.
When providing an outermost layer of two or more layers, a plurality of outermost layer coating solutions with different compositions and the like are divided into multiple times for each outermost layer coating solution to form an enteric layer. Just spray. For example, the composition of the outermost layer coating liquid sprayed directly on the enteric layer is a component that can function as a binder, a component that can function as an excipient, a component that can function as a lubricant, and a component that can function as a colorant. And a composition containing water.

(Granule)
The volume average particle diameter (D50) of the granule is preferably 1 mm or less, more preferably 750 μm or less, and further preferably 500 μm or less from the viewpoint of acid resistance.
In addition, as a measuring method of the volume average particle diameter (D50) here, there is a laser diffraction type particle size distribution measuring method, and a specific example is a laser diffraction scattering type particle size distribution measuring apparatus (SALD-2300 type, Shimadzu Corporation). It shows the value measured by (made).

The granule is formed by coating mannitol core particles having a particle size larger than 150 μm and not larger than 250 μm with a main drug layer containing duloxetine hydrochloride, and covering the coated main drug layer with a separation layer, and coating the separated layer with an enteric layer. Further, it can be prepared according to a known method such as coating and optionally coating the coated enteric layer with the outermost layer.
The method of coating the core particles with the main drug layer, the method of coating the coated main drug layer with the separation layer, the method of coating the coated separation layer with the enteric layer are not particularly limited, and a known method should be used. Can do. For example, fluid bed granulation method, stirring granulation method, spray drying and the like can be mentioned.

  When formulating with granules, other pharmacologically acceptable additives for formulation can be contained as extragranular components. Other pharmaceutical additives include binders such as hydroxypropylcellulose and hydroxypropylmethylcellulose, excipients such as mannitol and lactose, lubricants such as talc and magnesium stearate, low-substituted hydroxypropylcellulose, partial alpha In addition to disintegrants such as modified starch, known ingredients are commonly used as additives for pharmaceutical preparations generally used in the manufacture of pharmaceuticals such as sweeteners, flavoring agents, fluidizing agents, flavoring agents, and coloring agents. Ingredients known as pharmaceutical additives include components that can function as binders, excipients, lubricants, disintegrants, etc. One component has two or more functions. May be.

In order to formulate using granules, orally disintegrating tablets, tablets, capsules, dry syrups and the like can be mentioned, and orally disintegrating tablets are preferable.
When manufacturing an orally disintegrating tablet, the above-mentioned matters are applied as it is to a granule containing an active ingredient layer containing mannitol and duloxetine hydrochloride, a separating layer, an enteric layer and optionally an outermost layer.
Orally disintegrating tablets are additives for pharmaceutical preparations commonly used in the manufacture of pharmaceuticals such as disintegrants, lubricants, excipients, binders, sweeteners, flavoring agents, fluidizing agents, flavoring agents, and coloring agents. It may contain known components.

  As the disintegrant, known components can be used as long as they can function as a disintegrant. For example, starch such as corn starch and potato starch, partially pregelatinized starch, sodium carboxymethyl starch, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, crystalline cellulose, hydroxypropyl starch, starch Examples include sodium glycolate.

Among these disintegrants, crospovidone, croscarmellose sodium, and low-substituted hydroxypropylcellulose are more preferable from the viewpoint of disintegration.
As the disintegrant, any one disintegrant may be used alone, or two or more kinds may be used in combination.
The content of the disintegrant can be appropriately set, but is preferably 5% by mass or more and 25% by mass or less, and preferably 8% by mass or more and 20% by mass or less, based on the total mass of the granules. More preferably, it is 10 mass% or more and 20 mass% or less.

As the lubricant, known components can be used as long as they can function as a lubricant. Examples thereof include magnesium stearate, sodium stearyl fumarate, calcium stearate, sucrose fatty acid ester and the like.
Lubricants are formulated for the purpose of preventing powder from adhering to the mortar and pestle during tableting. However, if the lubrication effect is too strong, the moldability will be weakened and a practical tablet hardness will be obtained. High tableting pressure must be applied. Tablets that have been compressed with high pressure tend to have a slow disintegration rate, and therefore need to be compressed with the lowest possible pressure. In this respect, magnesium stearate that can obtain a lubricating effect even in a small amount is preferred.

The content of the lubricant can be appropriately set, but it is preferably 0.3% by mass or more and 5% by mass or less, and 0.3% by mass or more and 3% by mass or less with respect to the total mass of the granule. It is preferable that it is 0.3 mass% or more and 2.5 mass% or less.
If it is this range, adhesion of the tablet component to a tableting machine will be suppressed.

As the excipient, known ingredients can be used as long as they can function as excipients. Examples include sugar, sugar alcohol, crystalline cellulose, anhydrous calcium hydrogen phosphate, magnesium aluminate metasilicate, and the like.
Examples of the sugar alcohol include mannitol, erythritol, isomalt, lactylol, maltitol, sorbitol, xylitol and the like. Among these sugar alcohols, mannitol and erythritol are preferable, and mannitol is more preferable from the viewpoint of solubility of the orally disintegrating tablet.

Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxyvinyl polymer, carmellose sodium, pregelatinized starch, polyvinylpyrrolidone, gum arabic powder, gelatin, pullulan, polyvinyl alcohol and the like.
The additive for a formulation may be used individually by 1 type, and may be used in combination of 2 or more type.
The content of the formulation additive can be appropriately determined in consideration of the content of duloxetine hydrochloride, the daily dose, the particle size, and the like.

  The content of duloxetine hydrochloride relative to one orally disintegrating tablet preferably contains 22.4 mg to 33.7 mg of duloxetine hydrochloride (20.0 mg to 30.0 mg as duloxetine).

  The size and shape of the orally disintegrating tablet are not particularly limited as long as it is pharmaceutically acceptable. In the case of a round tablet, the diameter is 7 mm to 12 mm, the thickness is 3.0 mm to 7.0 mm, preferably 8 mm to 11 mm, the thickness is 3.5 mm to 6.5 mm, etc. : 4 mm to 8 mm, major axis 8 mm to 18 mm, preferably minor axis: 4 mm to 6.5 mm, major axis: 8 mm to 15 mm, etc., thickness 3.0 mm to 7.0 mm, preferably 3.5 mm to 6.5 mm Etc.

In addition, the hardness of the orally disintegrating tablet is not particularly limited. For example, in the case of a circular shape having a tablet diameter of about 8 mm to 11 mm, from the viewpoint of disintegration, transport stability, availability of an automatic packaging machine, etc. It can be set to 2 kgf or more, 3 kgf or more, or 5 kgf or more, and can be 8 kgf or less, 6 kgf or less, or 5 kgf or less as measured by a meter. Within this range, practically sufficient moldability and tablet strength can be obtained, and good disintegration can be obtained.
In the present invention, the hardness of the tablet is a value measured with a tablet hardness meter (TH-303MP, manufactured by Toyama Sangyo Co., Ltd.).

  In the present specification, the disintegration time is defined as the time during which it was confirmed that a part of the tablet disintegrated in the oral cavity. Orally disintegrating tablet test No. 10, orally disintegrating tablet tester (ODT-101, manufactured by Toyama Sangyo Co., Ltd.) preferably has a tablet disintegration time of 30 seconds or less, more preferably 20 seconds or less. .

The method for producing the orally disintegrating tablet is not particularly limited, and a known method can be used. For example, a granule preparation and a pharmaceutical additive such as a disintegrant, a lubricant, an excipient, and a binder are mixed to obtain a mixture, and the resulting mixture is compressed with a tableting machine. Thus, an orally disintegrating tablet can be obtained.
The method for mixing the granule preparation and the additive for preparation is not particularly limited. For example, it can mix using well-known mixers, such as a fluid bed granulator.
Further, the method for tableting the obtained mixture is not particularly limited. For example, tableting can be performed using a known tableting machine such as a rotary tableting machine.

  The orally disintegrating tablet of the present invention can be packaged in a packaging material to form a pharmaceutical product. For example, in the case of a tablet, it may be packaged with a PTP sheet and further packaged with an aluminum pillow; it may be filled into a sealed bottle. In addition, the pharmaceutical product may or may not contain a desiccant. Since duloxetine hydrochloride in the orally disintegrating tablet of the present invention is stabilized, a desiccant is not essential for the pharmaceutical product, but the solid preparation of the present invention is more stabilized by using the desiccant. Can be made. The desiccant may be set, for example, in an aluminum pillow or bottle.

  Hereinafter, although an example etc. explain the present invention in detail, the present invention is not limited to this.

Example 1
(Manufacturing method of active ingredient layer coating particles)
Granules having the formulations shown in Table 3 were obtained. Specifically, 4.02 kg of D-mannitol core particles having a particle size of 210.13 μm were put into a composite fluidized bed granulator / dryer, and 763.8 g of hypromellose and a volume average particle size (D50) of 4.54 μm. Then, 4.51044 kg of duloxetine hydrochloride was added to purified water, and then 23.3642 kg of the active ingredient layer coating solution prepared by stirring and mixing was spray-dried to obtain a granulated product. The obtained granulated product was sized with a screen diameter of 0.5 mm to obtain granules coated with the main agent layer (hereinafter referred to as “main agent layer coating particles”).

(Method for producing separation layer coating particles)
After the sized main drug layer coating particles 9.2942 kg were put into a combined fluidized bed granulator / dryer, 1.005 kg of hypromellose, 2.00196 kg of sucrose, 1.005 kg of titanium oxide, and 2.9346 kg of talc were added to purified water. Then, 25.03656 kg of the separation layer coating liquid prepared by stirring and mixing was spray-dried to obtain a granulated product. The obtained granulated product was sized with a screen diameter of 0.5 mm to obtain granules coated with a separation layer (hereinafter referred to as separation layer coating particles).

(Method for producing enteric coating particles)
(Method for producing first enteric coating particles)
16.3212 kg of the sized separated layer coating particles were put into a combined fluidized bed granulator / dryer, and while spraying 201 g of talc, 381.9 mg of triethyl citrate and 3.76875 kg of hypromellose phthalate were added to absolute ethanol. After charging and stirring and mixing, 1.5075 kg of talc was charged and the first enteric layer coating solution prepared by stirring and mixing was spray-dried to obtain a granulated product. The obtained granulated product was sized with a screen diameter of 0.5 mm to obtain granules coated with a first enteric layer (hereinafter referred to as first enteric layer-coated particles).

(Method for producing second enteric coating particle)
While putting 18.18035 kg of the first enteric coated particle thus sized into a combined fluidized bed granulator / dryer, while spraying 201 g of talc, 381.9 g of triethyl citrate and 3.76875 kg of hypromellose phthalate Was added to absolute ethanol and mixed with stirring, and then the second enteric layer coating solution prepared by adding talc 1.5075 kg and stirred and mixed was spray-dried, and granules coated with the second enteric layer (hereinafter referred to as “enteric layer”) , Second enteric layer coating particles).

(Method for producing outermost layer coating particles)
The second enteric layer coating particle was charged with 201 g of hypromellose and 562.8 g of titanium oxide in purified water, and then the outermost layer coating solution prepared by stirring and mixing was spray-dried to obtain a granulated product. The obtained granulated product was sized with a screen diameter of 0.5 mm to obtain granules coated with the outermost layer (hereinafter referred to as granules).

(Comparative Example 1)
In Comparative Example 1, granules were obtained in the same manner as in Example 1 except that D-mannitol core particles having a particle diameter of 109.52 μm were used.

(Acid resistance test)
The acid resistance of the granules obtained in Example 1 and Comparative Example 1 was evaluated by the following procedure.
The granules of Example 1 and Comparative Example 1 are put in a capsule (product name: HPMC capsule, manufactured by Qualicaps Co., Ltd.) and dissolved for 60 minutes using the dissolution test apparatus 2 paddle method, dissolution test first solution (pH 1.2). The dissolution test for 120 minutes was carried out to evaluate the acid resistance.
As an acid resistance evaluation standard, when the acid resistance for 120 minutes was 5% or less, moisture permeation did not occur inside the granules, and as a result, it was judged that the enteric coating had sufficient acid resistance.
The test was conducted at 50 rpm with the paddle method using 900 mL (pH 1.2) of the first dissolution test solution.

  One capsule each containing the granules of Example 1 and Comparative Example 1 was taken, the test was started, and 10 mL of each eluate was accurately taken at a specified time and immediately heated to 37 ± 0.5 ° C. in advance. 10 mL of test solution was accurately and carefully supplemented. The collected eluate was filtered through a membrane filter having a pore size of 0.45 μm or less. Except for 5 mL of the first filtrate, the next filtrate was used as a sample solution.

  Separately, about 30 mg of duloxetine hydrochloride for quantification is accurately weighed and dissolved in 5 mL of methanol, and then water is added to make exactly 50 mL. 4 mL of this solution was accurately weighed, and the test solution was added to make exactly 100 mL, which was used as a standard solution.

Each of the sample solution and standard solution 10μL taken exactly was analyzed by liquid chromatography under the following conditions to measure the peak area A _T and A _S of duloxetine of the respective liquid.
〔Test conditions〕
Detector: UV absorptiometer (measurement wavelength: 230 nm)
Column: A stainless tube having an inner diameter of 4.6 mm and a length of 10 cm is filled with 5 μm of octylsilylated silica gel for liquid chromatography.
Column temperature: constant temperature around 45 ° C. Mobile phase: 3.4 g of potassium dihydrogen phosphate and 15 mL of triethylamine are dissolved in 1000 mL of water, and phosphoric acid is added to adjust to pH 5.5. To 600 mL of this solution, 300 mL of methanol and 100 mL of tetrahydrofuran are added.
Flow rate: Adjust so that the retention time of duloxetine is about 6 minutes.

[System compatibility]
System performance: When 10 μL of the standard solution is operated under the above conditions, the number of theoretical plates and the symmetry factor of the duloxetine peak are 2,000 or more and 2.0 or less, respectively.
System repeatability: When the test is repeated 6 times with 10 μL of the standard solution under the above conditions, the relative standard deviation of the peak area of duloxetine is 2.0% or less.

For quantification of the eluted duloxetine, the solution was filtered, and the peak area of the filtrate was measured by an automatic integration method. Table 4 shows the measurement results.
Amount of duloxetine (mg) = M _S × (A _T / A _S ) × 0.8 × 0.891
M _S: Duloxetine balance of hydrochloric acid salt-up amount (mg)
0.8: (dilution ratio of sample solution / dilution ratio of standard solution)
0.891: (molecular weight of duloxetine / molecular weight of duloxetine hydrochloride)

From the above results, it was found that the granule of Example 1 had very excellent acid resistance because the dissolution rate was 5% or less after 60 minutes and after 120 minutes.
On the other hand, the granule of Comparative Example 1 was found to have poor acid resistance because the dissolution rate was 5.2% after 60 minutes and the value for 120 minutes was 13.4%, which was 5% or more.

Next, an orally disintegrating tablet having the formulation shown in Table 5 was obtained using the granule of Example 1 having excellent acid resistance. Specifically, the granule 28.8033 kg of Example 1, D-mannitol 27.723528 kg, carmellose 9.90126 kg, crospovidone 3.588252 kg, crystalline cellulose 9.90126 kg, and talc 80.4 g were mixed in a container rotating type mixer. And mixed for 10 minutes. Thereafter, 643.2 g of magnesium stearate was added and mixed. The mixed product was tableted with a tableting pressure of 1450 kgf using a rotary tableting machine to obtain an orally disintegrating tablet with a tablet mass of 600.0 mg.
The hardness of the obtained orally disintegrating tablet was measured using a tablet breaking strength meter TH-303MP (manufactured by Toyama Sangyo Co., Ltd.).

(Evaluation of disintegration)
The disintegration time of the obtained orally disintegrating tablet was measured. The disintegration time was measured using an orally disintegrating tablet testing machine (ODT-101, manufactured by Toyama Sangyo Co., Ltd.). Specifically, a tablet is fixed to a sample stage of a measuring device with a load jig (weight) of 15 g / φ20 mm, and a load jig at 30 rpm is provided while supplying 37 ° C. purified water as a test solution to the tablet. Was rotated and the time until the tablet disintegrated was measured.
As a result of measurement, the disintegration time was 25 seconds, and it was found that the disintegration was excellent.

(Evaluation of taking feeling)
Moreover, when the obtained orally disintegrating tablet was dissolved in the mouth, a powdery taste and a rough feeling were hardly felt, and it was found that the taste and the touch feeling were excellent.

Claims (1)

(A) a core particle composed of mannitol having a particle size of greater than 150 μm and less than 250 μm;
(B) an active ingredient layer in which the core particles are coated with duloxetine hydrochloride;
(C) a separation layer covering the active ingredient layer;
(D) an enteric layer covering the separation layer;
An orally disintegrating tablet comprising granules consisting of